DDB2

Official Full Name

damage specific DNA binding protein 2

Organism

Homo sapiens

GeneID

1643

Background

This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

Synonyms

XPE; DDBB; UV-DDB2;

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Detailed Information

The damage-specific DNA binding protein (DDB2) gene is a crucial player in the cellular response to DNA damage and repair process. Post-translationally modified DNA repair proteins are essential for maintaining genome stability and preventing the development of various diseases, including cancer.

Structure And Function of DDB2

The DDB2 gene encodes a protein of approximately 56 kDa, which is highly conserved across various species, including humans, mice, and yeast. The protein consists of several distinct domains that confer distinct functionalities. The N-terminal region contains a leucine-rich repeat (LRR) domain, which is responsible for DNA binding and recognizing damaged DNA. The central region consists of a cysteine-rich domain (CRD), which is involved in protein-protein interactions and plays a role in the assembly of repair complexes. The C-terminal region contains a transactivation domain (TAD), which is involved in the transcriptional activation of target genes.

DDB2 is a damage-specific DNA binding protein that binds to damaged DNA and recruits other repair proteins to the sites of damage. It plays a critical role in the recognition and repair of UV-induced DNA lesions, as well as other types of DNA damage. In humans, the DDB2 gene is located on chromosome 11 and is encoded by 15 exons. The protein is expressed in various tissues, with the highest levels detected in the skin, liver, and testis.

Regulation of DDB2

The expression of the DDB2 gene is tightly regulated under various environmental conditions and during cellular processes. Transcription of the DDB2 gene is induced by DNA damage, particularly UV radiation, and transcription factors such as ATF4 and CREB. Post-translational modifications, including phosphorylation and ubiquitination, also play a crucial role in regulating DDB2 activity and stability. For example, phosphorylation of DDB2 at Serine 70 by CDK2 and CDK4 promotes its stability and activity during DNA repair. On the other hand, ubiquitination by the E3 ubiquitin ligase MDM2 targets DDB2 for degradation, thereby regulating its availability for DNA repair.

Clinical Significance of DDB2

Defects in the DDB2 gene can lead to impairments in DNA repair and increased susceptibility to various diseases, including cancer. Inactivating mutations in the DDB2 gene have been identified in patients with skin cancer, indicating a role for the protein in tumorigenesis. Moreover, reduced expression of DDB2 has been associated with increased risk of developing squamous cell carcinoma, suggesting that the protein serves as a tumor suppressor.

Overexpression of DDB2 has also been reported in various cancers, including breast, colon, and lung cancer. In these cases, DDB2 appears to contribute to tumorigenesis by promoting DNA repair and enabling cells to survive DNA damage. Consequently, inhibition of DDB2 expression or activity has been proposed as a potential therapeutic strategy for cancer treatment.

Reference:

Bao, Ning et al. "A protein with broad functions: damage-specific DNA-binding protein 2." Molecular biology reports vol. 49,12 (2022): 12181-12192. doi:10.1007/s11033-022-07963-4

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